Diabetes is the fifth leading cause of death in the United States based on death certificate data from 2005, which specifically linked type 2 diabetes mellitus (T2DM) to more than 233,619 deaths. Over 23.5 million Americans 20 years of age and older (~11% of the population in this age group) have diabetes, 1.6 million new cases of T2DM were diagnosed in this population in 2007 and the total (direct and indirect) annual cost in 2007 to treat all cases of Diabetes in the United States was estimated at over $174 billion. Skeletal muscle insulin resistance and T2DM have been shown to result from genetic origins as well as from environmental factors such as alterations in dietary composition and/or lack of physical activity. However, it has not been fully resolved exactly how impairments in skeletal muscle insulin signaling are manifested and if these defects are entirely reversible. It has been noted that a link may exist between obesity, chronic low-grade inflammation and skeletal muscle insulin resistance, and we have recently reported that in the skeletal muscle of the high fat-fed rat (an "environmental" model of insulin resistance) that activation of inflammatory pathways appear to contribute to impairing insulin-stimulated activation of phosphoinositide 3-kinase [PI3-K] activity. In this project we will direct our attention on inflammatory mechanisms in the regulation of insulin signaling in skeletal muscle and will specifically focus on the temporal relationship between the inflammatory signaling cascades and PI3-K activation, and if attenuation of the inflammatory response that arises from the provision of a high fat diet improves insulin-stimulated PI3-K activation. Our hypothesis is that there is a strong temporal relationship between increased inflammatory pathway activation and decreased insulin-stimulated PI3- K activation in high fat-fed rodent skeletal muscle, but if the activation of specific components of the inflammatory pathways can be disrupted that insulin-stimulated PI3-K activation can be rescued. The specific aims of this application are: 1) To identify how the provision of a high fat diet temporally activates the inflammatory pathways and in turn contribute to impairing insulin-stimulated PI3-K activation in the skeletal muscle of the Sprague-Dawley rat, and 2) To identify what component(s) of the inflammatory pathways must be activated in order for insulin-stimulated PI3-K activation to be impaired in high fat-fed rodent skeletal muscle. PUBLIC HEALTH RELEVANCE: A high fat diet decreases the ability of insulin to effectively regulate skeletal muscle carbohydrate metabolism, but the mechanism behind this effect is not fully understood. It is thought that a high fat diet causes an inflammatory response in the skeletal muscle that in turn impairs insulin action. This project will evaluate the relationship between increased inflammatory pathway activation and decreased insulin signaling in the skeletal muscle of the high fat-fed rat and then systematically examine specific components of the inflammatory pathways to identify which inflammatory signal(s) contribute to impairing insulin signaling in high fat-fed rodent skeletal muscle.